Division of Medicinal Chemistry Abstracts-235th ACS National ...

MEDI 11
Calcitonin gene-related peptide (CGRP) receptor antagonists for the treatment of
migraine: Development of orally bioavailable imidazoazepanes
Daniel V. Paone, Department of Medicinal Chemistry, Merck Research Laboratories, 770
Sumneytown Pike, West Point, PA 19486, daniel_paone@merck.com
Calcitonin gene-related peptide (CGRP) is a 37 amino acid neuropeptide that has been
implicated in the pathogenesis of migraine. Since CGRP receptor antagonists promote
normalization of dilated blood vessels through a non-vasoconstrictive mechanism, this class of
compounds could prove effective in the relief of migraine without the adverse cardiovascular
effects that are sometimes associated with existing therapies. Our research program targeted
non-peptide, orally bioavailable CGRP receptor antagonists culminating in the discovery of
caprolactam-azabenzimidazolone MK-0974, which has recently demonstrated efficacy in a
Phase IIb clinical trial. Targeted areas for improvement in our backup program include aqueous
solubility, in vivo potency, and rhesus pharmacokinetics. We have identified a series of
imidazoazepanes which demonstrate improved potency and aqueous solubility. Concurrently,
an investigation of replacements for the metabolically labile azabenzimidazolone of MK-0974
has produced a series of spiropiperidines with superior pharmacokinetic profiles. This strategy
ultimately resulted in the identification of backup MK-2918.
MEDI 12
Novel series of CB2 selective agonists for the treatment of neuropathic pain
Philippe Diaz, Jijun Xu, Fanny Astruc Diaz, Hao-Min Pan, and Mohamed Naguib,
Anesthesiology and Pain Medicine - Research, The University of Texas M.D. Anderson Cancer
Center, Unit 110, 1515 Holcombe Blvd, Houston, TX 77030, Fax: 713-794-4590,
pdiaz@mdanderson.org
Neuropathic pain, a debilitating condition characterized by severe, persistent pain that is
refractory to traditional analgesia, results from heterogeneous conditions affecting the peripheral
or central nervous system (CNS) and affects an estimated 8% of people worldwide. The
cannabinoid receptor CB2, has emerged as a new target for the treatment of pain without the
CB1 mediated psychotropic side effects. Two series of novel cannabinoid modulators based on
two heterocyclic scaffolds, have been synthesized. Highly potent and selective CB2 agonists
were identified in both series using in vitro binding and functional assays. Selected compounds
were tested in vivo relevant models of neuropathic pain and were able to reverse allodynia and
hyperalgesia, with no visible CNS side effects. In contrast, a CB1–CB2 agonist, Win 55,212,
caused rigidity, spasm, and lethargy. Details of the synthesis, CB1 and CB2 receptors structureactivity
relationships, in vitro, and in vivo data will be presented.